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Monoclonal immunoglobulin deposition disease (MIDD) is a rare disease characterized by the deposition of monoclonal Ig molecules in basement membranes. In contrast to amyloidosis, the deposits in MIDD are nonfibrillar and Congo-red negative. MIDD includes three subtypes depending on the composition of deposits: light chain deposition disease (LCDD), the most common subtype, in which the deposits are composed of monoclonal light chains only; light and heavy chain deposition disease (LHCDD), in which the deposits are composed of monoclonal light and heavy chains; and heavy chain deposition disease (HCDD), in which the deposits are composed of monoclonal heavy chains only. The monoclonal light chains in LCDD are mainly of the κ isotype (92%), and the majority belong to the VκIV subgroup [rx,rx]. The deposits in HCDD are composed of the γ heavy chain, which typically lacks the first constant domain (CH1) [rx,rx,rx]. Renal involvement is almost always present in MIDD. Patients typically present with renal insufficiency and proteinuria, often accompanied by nephrotic syndrome. The characteristic morphologic features of renal MIDD include the following: nodular sclerosing glomerulopathy by light microscopy; diffuse linear staining of glomerular basement membranes (GBMs) and tubular basement membranes (TBMs) for a single light chain (LCDD), a single light chain and a single heavy chain (LHCDD), or a single heavy chain without light chains (HCDD) by immunofluorescence; and nonfibrillar, “powdery” electron-dense deposits in GBMs and TBMs detected by electron microscopy [rx].
Heavy-chain deposition disease (HCDD) is the least common non-organized monoclonal immunoglobulin deposition disease (MIDD), with only 23 documented cases in world literature to date. Unlike the more common light chain immunoglobulin deposition disease, an association of multiple myeloma or plasma cell dyscrasias with HCDD is less common, with only 7 of 23 (30%) reported cases being associated with the development of demonstrable monoclonal plasmacytosis. Nodular glomerulosclerosis is the classic glomerular pattern of injury of all monoclonal immunoglobulin disorders, and the disease (though suspected on light microscopy) can be conclusively diagnosed only by an extended panel of immunofluorescence that includes antibodies against heavy-chain isotypes and heavy-chain constant domains. γ heavy-chain deposition is the most common among these; however, deposition of α- [rx, rx] and µ- [rx, rx] heavy chains is also reported.
- Heavy chain deposition disease (HCDD)
- Immunoglobulin deposition disease
- Light and heavy chain deposition disease (LHCDD)
- Light chain deposition disease (LCDD)
- Monoclonal immunoglobulin deposition disease (MIDD)
- Primary amyloidosis
- Randall disease
- Systemic light chain disease
Clinical presentation of Monoclonal Immunoglobulin Deposition Disease (MIDD)
Although HCDD as well as other MIDDs are systemic diseases with deposition of abnormal Igs in a variety of organs, it is the deposition of abnormal immunoglobulins in the renal parenchyma which most often leads to clinical dysfunction. Extra-renal deposits in HCDD are very uncommon; however, they have been reported in the heart [rx], joints [rx–rx], skin, striated muscle [rx], pancreas and thyroid as well as liver. Most of the non-renal visceral organ depositions are usually asymptomatic, and hence the incidence of these deposits is likely to be under-estimated. Skin is the next common organ to be affected by HCDD, with α-HCDD being the commonest and less commonly γ-HCDD presenting as cutis laxa [rx, rx, rx]. Deposition of abnormal chains in LCDD and LHCDD has been documented in the liver and heart ∼25% cases [rx]. Mild alterations in the liver function tests are common, but hepatic failure is distinctly rare. In the liver, deposition of abnormal immunoglobulins is commonly minimal and sinusoidal but can be massive.
Renal involvement is a constant feature in HCDD with most patients presenting with renal failure (∼90% cases), recent onset hypertension (∼70% cases) and proteinuria (80%) most of whom had nephrotic range proteinuria (60%). Most patients present with rapidly progressive renal failure. Hematuria is variably present in 25% of cases reported to date. The manifestation of HCDD are very similar to other MIDD, except for a stronger association with hypertension, glomerulosclerosis and hematuria [rx].
Nodular glomerulosclerosis is the classical histological pattern, although other patterns like the crescentic pattern of glomerular injury [rx, rx], as well as a predominantly diffuse proliferative pattern of injury, is also reported. No cases have been reported of pure HCDD with either membranous pattern of injury or normal morphology on light microscopy. The glomeruli show nodular mesangial expansion by deposition of Periodic Acid Schiff (PAS) positive material which is Congo-red negative, can be fuschinophilic on trichrome stain and stains avidly with silver stains, unlike amyloid which is only weakly PAS-positive and silver negative in addition to being congophilic and showing apple-green birefringence. Nodular glomerulosclerosis brings a histological differential diagnosis of diabetic nephropathy, membranoproliferative glomerulonephritis (GN), amyloidosis and Congo-red-negative amyloid-like deposits (fibrillary GN, immunotactoid GN), MIDD of either LCDD or LHCDD type, idiopathic type I or III collagen fibrotic GN and fibronectin GN. Milder forms of the disease may show only a mild increase in a mesangial matrix with basement membrane thickening. Although the glomerular disease is the most common reason for clinical impairment, HCDD is not a pure glomerular disease. Tubular lesions are usually present in the form of PAS-positive, refractile thickening of the tubular basement membrane. There is some predominance of deposition in the distal tubules and loop of Henle. Advanced cases usually have significant fibrosis.n).
An appropriate immunofluorescence evaluation is essential in diagnosing HCDD and differentiating it from its other differential diagnoses. The diagnosis may be suspected in an initial panel that does not include the IgG/IgA subtypes when anti-IgG/IgA is positive while there is no light-chain positivity. The definitive diagnosis however requires demonstration of monoclonality of the heavy chains by using a wider immunofluorescence panel of antibodies identifying distinctly the four IgG subtypes and/or two IgA subtypes. Since there is only one IgM subtype, the presence of IgM positivity without any light-chain positivity should lead to a diagnosis. Any of the IgG or IgA subtypes may be present. The most common IgG subtype implicated is the IgG1 (8 of 24 cases) among all the cases reported to date with IgG4 being the next most common (4 of 24). Positivity is usually linear with stronger positivity in the glomerular basement membrane when compared with the mesangial nodules. Positivity along the tubular basement membrane is a rule. Similar positivity may be seen within the blood vessels. Complement positivity is variable with maximum positivity being seen in cases with IgG1 and IgG3. Demonstration of deletion of CH1 domain of the IgG is however not necessary for the diagnosis. The deletion of the CH1 domain has been documented in all cases which were evaluated using antibodies specific to each CH domain.
Transmission electron microscopy demonstrates the deposition of non-fibrillar, powdery, electron-dense deposits along the tubular basement membrane, glomerular basement membrane, and blood vessels. The deposits usually form a continuous band on the endothelial aspect of the glomerular basement membrane and on the outer aspect of the tubular basement membrane, facing the interstitium. But unlike amyloid deposits, they do not invade into the lamina densa. Deposits may also be found in the Bowman’s capsule. Immunoelectron microscopy can be helpful in difficult cases.
Treatment of Monoclonal Immunoglobulin Deposition Disease (MIDD)
No renal follow-up data were available for four patients, and four patients died within 1 month after kidney biopsy. The remaining 56 patients (88%) were followed for a mean of 34 months (median 25; range, 1–140). Eight patients (14%) were not treated with chemotherapy, five of whom (63%) progressed to ESRD. Thirty-two patients (57%) were treated with chemotherapy, 11 of whom (34%) progressed to ESRD. Chemotherapy consisted of dexamethasone alone in two patients; melphalan and dexamethasone in six; melphalan, cyclophosphamide, and dexamethasone in two; melphalan, bortezomib, and dexamethasone in three; melphalan, thalidomide, and dexamethasone in one; cyclophosphamide and dexamethasone in one; dexamethasone and thalidomide in three; bortezomib and dexamethasone in four; dexamethasone, thalidomide, and bortezomib in three; cyclophosphamide, bortezomib, and dexamethasone in two; azathioprine and dexamethasone in one; lenalidomide and dexamethasone in three; and rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone in one with lymphoma. The remaining 16 patients (29%) were treated with autologous stem cell transplant (SCT), 6 of whom (38%) progressed to ESRD.
Most patients reported have been treated with pulse methylprednisolone or with a combination of methylprednisolone and melphalan. Many patients also received other cytotoxic agents such as cyclophosphamide or chlorambucil, with just an occasional patient having received dexamethasone, thalidomide or bortezomib. Among all 24 cases recorded in the literature to date, just 3 cases responded apparently completely to the treatment given, which included melphalan and methylprednisolone in 2 cases [rx–rx] and low-dose steroids in the third [rx]. Only one of these cases [rx] has been shown to be free of disease 2 years after the initial diagnosis on a follow-up biopsy. Another three cases showed partial improvement of symptoms and laboratory values, one of which was treated with melphalan along with cyclophosphamide, another with melphalan alone [rx], while the third patient received combination chemotherapy with vincristine, adriamycin and dexamethasone, followed by autologous blood stem cell graft [rx]. One patient [rx] showed stable disease at 2 years of follow-up despite not receiving any therapy. The remaining 18 of 24 patients failed to show any response to treatment, most of whom received a combination of methylprednisolone with melphalan and/or other chemotherapeutic agents like cyclophosphamide, vincristine, adriamycin, chlorambucil etc. Our patient was treated with thalidomide with dexamethasone, but showed progressive worsening of renal failure and proteinuria at the last follow-up, 8 months after diagnosis. Significant long-term follow-up is unavailable in nearly all cases.
It is possible that the patients who responded completely (clinically as well as pathologically) or partially to treatment were in the initial stages of the disease as suggested by Soma et al. . The response to treatment would probably also depend on the presence of an overt plasma cell dyscrasia. Whether patients with HCDD are poor candidates for renal transplantation is unknown; however, one patient who received renal graft, developed recurrent disease 2½ years post-transplant .